Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D 3 analogue, in a phase I study of patients with advanced malignancies Journal Article
| Authors: | Wieder, R.; Novick, S. C.; Hollis, B. W.; Bryan, M.; Chanel, S. M.; Owusu, K.; Camastra, D.; Saunders, T.; Pliner, L.; Harrison, J.; Bonate, P.; Williams, T.; Soignet, S. |
| Article Title: | Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D 3 analogue, in a phase I study of patients with advanced malignancies |
| Abstract: | Purpose: Differentiation therapy is an alternative to chemotherapy with potentially less toxicity, improved quality of life, and survival. We conducted a phase I trial of ILX23-7553, a formulation of 1,25-dihydroxy-16-ene-23- ynevitamin D3, a 1,25-dihydroxyvitamin D3 analog with preclinically demonstrated antitumor and differentiating effects and diminished hypercalcemic effects. Patients and methods: The protocol consisted of five daily oral treatments during 14-day cycles at 15 dose levels from 1.3 to 45.0 μg/m2/day. We treated 42 heavily pretreated patients who had a variety of malignancies with 162 treatment cycles, and obtained pharmacokinetics from three patients at the two highest dose levels. Results: There were no grade 3 or 4 toxicities. Grade 1-2 toxicities included diarrhea, nausea, fatigue, constipation, and one grade 1 hypercalcemia. Average day 6 calcium was 9.26 ± 0.55 mg/dl in cycle 1 and 9.30 ± 0.67 mg/dl in cycle 2. Pharmacokinetics at dose levels 14 (40 μg/m2/day) (1 patient) and 15 (45 μg/m2/day) (2 patients) demonstrated an average Cmax of 30.4 ± 7.8 pg/ml (0.07 nM) and 104 ± 38.2 pg/ml (0.25 nM), and AUCs of 222.5 ± 225.2 pg · h/ml and 855 ± 536 pg h/ml, respectively. Eight patients (19%) had stable disease. While in vitro effects have been reported at these concentrations, they were at least 10-fold lower than ED50S, and the study was terminated before an MTD was reached. Conclusion: The drug is safe and has potential benefits at serum concentrations where effects begin to be noted in vitro. Further study is needed with a reformulated higher unit dose compound to determine the safety and efficacy of higher serum concentrations. |
| Keywords: | adult; cancer chemotherapy; clinical article; controlled study; aged; aged, 80 and over; middle aged; clinical trial; constipation; fatigue; squamous cell carcinoma; area under the curve; diarrhea; drug safety; liver cell carcinoma; neoplasms; adenocarcinoma; melanoma; metastasis; quality of life; controlled clinical trial; pain; gastrointestinal symptom; lung non small cell cancer; nausea; calcium; hypercalcemia; in vitro study; drug effect; kidney carcinoma; colorectal carcinoma; breast carcinoma; lymphoma; response; ovary carcinoma; muscle weakness; mitomycin c; carcinoid; area under curve; thyroid carcinoma; headache; drug dose; maximum tolerated dose; phase 1 clinical trial; leiomyosarcoma; bladder carcinoma; dyspepsia; uterus myoma; abdominal cramp; esophagus carcinoma; concentration response; liposarcoma; uterine cervix carcinoma; differentiation; drug formulation; prostate carcinoma; vagina carcinoma; gastrointestinal diseases; cholecalciferol; testis carcinoma; vitamin d3; advanced malignancies; cancer; humans; human; male; female; priority journal; article; 9,10 secocholesta 5,7,10(19),16 tetraen 23 yne 1,3,25 triol; butylated hydroxyanisole; butylcresol; calcitriol derivative; ilx 23 7553; miglyol |
| Journal Title: | Investigational New Drugs |
| Volume: | 21 |
| Issue: | 4 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2003-11-01 |
| Start Page: | 445 |
| End Page: | 452 |
| Language: | English |
| DOI: | 10.1023/a:1026203418976 |
| PUBMED: | 14586212 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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